New meso-azacyclic aromatic acid amides and esters as novel serotonergic agents

ABSTRACT

The meso-azacyclic aromatic acid amides and esters of the present invention are useful in the treatment of the central nervous system and gastrointestinal motility disorders such as gastroesophageal reflux, non-ulcer dyspepsia, delayed gastric emptying, ileus, irritable bowel syndrome, and the like. Additionally, the compounds of the present invention find utility as antagonists of serotonin 5-HT 3  receptors. As such they are useful for the treatment of humans and animals wherein antagonism of 5-HT 3  receptors is beneficial. Therapy is indicated for, but not limited to, the treatment of anxiety, psychoses, depression (especially depression accompanied by anxiety), cognitive disorders, substance abuse dependence and/or withdrawal, irritable bowel syndrome, emesis caused by chemotherapeutic agents, and visceral pain. Additionally, the compounds of the present invention may find utility as enhancers of nasal absorption of bioactive compounds.

This is a divisional application of application Ser. No. 08/234,336,filed on Apr. 28, 1994, which is a divisional of application Ser. No.07/973,090 filed as PCT/US92/01525, Mar. 4, 1992, now issued as U.S.Pat. No. 5,318,977, which is a continuation of International ApplicationSer. No. 92/01525, filed Mar. 4, 1992, which is a continuation-in-partof application Ser. No. 07/666,151, filed Mar. 7, 1991, now abandoned.

BACKGROUND OF THE INVENTION

The invention herein is directed to compounds and a method of treatinggastrointestinal motility disorders of a mammal by administering to themammal in need thereof a therapeutically effective amount of a compounddisclosed herein or a pharmaceutically acceptable salt thereof. Themethod can be practiced to treat gastrointestinal motility disorderssuch as gastroesophageal reflux, diseases characterized by delayedgastric emptying, ileus, irritable bowel syndrome, and the like. Thecompounds of the invention are serotonergic 5-HT₃ antagonists and assuch are useful for the treatment of conditions, for example, such asanxiety, psychoses and depression.

There are classes of compounds known for the treatment of suchdisorders. For example, azatetracycle compounds are disclosed inco-pending U.S. patent application Ser. No. 07/515,391 filed Apr. 27,1990, and N-Azabicyclo [3.3.0] octane amides of aromatic acids aredisclosed in co-pending application Ser. No. 07/406,205 filed Sep. 11,1989.

Aza-adamantyl compounds are disclosed in U.S. Pat. No. 4,816,453 and arementioned generically in U.K. Patent 2,152,049A and European application0189002A2.

Azabicyclic nonanes are disclosed in European Patent application0094742A2. Additional azabicyclic compounds are disclosed in U.S. Pat.Nos. 4,797,387 and 4,797,406.

Benzamides have been known as 5-HT₃ antagonists and as compoundspossessing gastrointestinal motility-enhancing properties. Benzamides ofthe following formula: ##STR1## compounds wherein X can be anazabicycloalkane moiety and which exhibit gastrointestinal motilityenhancing and/or 5-HT₃ antagonist properties are disclosed in EP0094742A2 and in U.S. Pat. No. 4,797,406. In addition, UK Patent2,152,049 discloses that certain benzamide derivatives exhibit serotoninM antagonistic activity.

Indoleamides of the following formula have also been described aspossessing gastrointestinal motility-enhancing and/or 5-HT₃ antagonistproperties: ##STR2##

Compounds wherein X contains an aminergic side chain or anazabicycloalkane moiety are described in U.S. Pat. No. 4,797,406.

European patent publication number 0,230,718 discloses certainsubstituted benzamide derivatives, substituted with piperidinylanalogues as having gastrointestinal motility-enhancing and/orantiemetic activity and/or 5-HT receptor antagonist activity.

J. Heterocyclic Chemistry (1987) 24:47 describes the preparation of thefollowing compound: No substitution is shown in the phenyl ring and noutility is described. ##STR3##

J. Pharmaceutical Sciences (1987) 76:416 describes compounds of genericscope. Utility as anti-arrhythmic agents is described. ##STR4##

n=1 or 2

R₁ =H, 2-Me, 4-NH₂, 4-OMe, 4-NHCO₂ Et, 2-OEt, 4-OEt, 3- or 4-NMe₂, 3- or4-NO₂ ; R₂ =H or 6-Me.

JP Patent 58083694 A2 and JP 0027355B describe anti-arrhythmic agents ofthe following formula wherein n=1 or 2; R₁ or R₂ are both Me or R₁ is Hwhile R₂ is nitro, di-lower alkylamino, lower alkoxycarbonylamino, orethoxy. ##STR5##

EP Patent 39,903 and U.S. Pat. No. 4,617,401 describe compounds of thefollowing formula wherein R is H, OMe, OH, or NH₂ ; X is NH or O; and Zis a lone electron pair or optionally substituted alkyl group. Thecompounds are described as spasmolytic, antiarrhythmic, andneuromuscular-blocking agents. ##STR6##

SUMMARY OF THE INVENTION

The compounds of the present invention are useful in the treatment ofgastrointestinal motility disorders such as gastroesophageal reflux,non-ulcer dyspepsia, delayed gastric emptying, ileus, irritable bowelsyndrome, and the like. Additionally, the compounds of the presentinvention find utility as antagonists of serotonin 5-HT₃ receptors. Assuch they are useful for the treatment of humans and animals whereinantagonism of 5-HT₃ receptors is beneficial. Therapy is indicated for,but not limited to, the treatment of anxiety, psychoses, depression(especially depression accompanied by anxiety), cognitive disorders,substance abuse dependence and/or withdrawal, irritable bowel syndrome,emesis caused by chemotherapeutic agents, and visceral pain.Additionally, the compounds of the present invention may find utility asenhancers of nasal absorption of bioactive compounds.

DETAILED DESCRIPTION OF THE INVENTION

The invention herein is directed to compounds of formula I:

    Ar--(CO--X).sub.p --Z                                      I

the stereoisomers and pharmaceutically acceptable salts thereof whereinp is 0 or 1 and when p is 0, Ar represents a radical of the formula:##STR7## and when p is 1, Ar represents a radical of the formula:##STR8##

Wherein Y is NH; R₁ is C₁₋₆ alkoxy; R₂ and R₃ are independently H,halogen, CF₃, hydroxyl, C₁₋₂ alkoxy, C₂₋₇ acyl, amino, amino substitutedby one or two C₁₋₆ alkyl groups, C₂₋₇ acylamino, aminocarbonyl, oraminosulfone optionally substituted by one or two C₁₋₆ alkyl groups,C₁₋₆ alkylsulfone, or nitro; R₄ is H, halo, or C₁₋₆ alkoxy; R₅ and R₆are the same or different and can be H, halo, CF₃, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylthio, C₁₋₇ acyl, C₁₋₇ acylamino, C₁₋₆alkylsulfonylamino, N-(C₁₋₆ alkylsulfonyl)-N-C₁₋₄ alkylamino, C₁₋₆alkylsulfinyl, hydroxy, nitro, or amino, aminocarbonyl, aminosulfonyl,aminosulfonylamino, or N-(aminosulfonyl)-C₁₋₄ alkylamino optionallyN'-substituted by one or two groups selected from C₁₋₆ alkyl, C₃₋₈cycloalkyl, phenyl, or phenyl C₁₋₄ alkyl groups or optionallyN'-disubstituted by C₄₋₅ polymethylene; R₇ and R₁₀ can be the same ordifferent and can be H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₄ alkyl or togetherare C₂₋₄ polymethylene; R₈ and R₉ can be the same or different and canbe H, C₁₋₄ alkyl or taken together are a covalent bond; R₁₁ is H orhalogen; R₁₂ and R₁₂ ' are the same or different and can be H, C₁₋₆alkyl, or phenyl C₁₋₄ alkyl; R₁₃ and R₁₄ can be the same or differentand can be H, halo, CF₃, C₁₋₆ alkyl, C₁₋₇ acyl, C₁₋₇ acylamino, oramino, aminocarbonyl or aminosulfonyl, optionally substituted by one ortwo C₁₋₆ alkyl or C₃₋₈ cycloalkyl groups, or by C₄₋₅ polymethylene orbiphenyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, hydroxy, or nitro, or when R₁₃ and R₁₄ are taken together aremethylenedioxy or ethylenedioxy; A₁ is O, S, N(R₁₂), or CH₂ ; A₂ isC--OR₁₂, N+----O--, CO₂ R₁₂, CONR₁₂ (R₁₂ '), SR₁₂, or SO₂ NR₁₂ (R₁₂ ');A₃ is N or CH;

X is NH or O; and

Z represents a radical of the formula: ##STR9##

Wherein m is 1 or 2, n is 0 or 1, p is 1 or 2, q is 1 or 2, and r is 0or 1.

The term "cycloalkyl" embraces cyclic radicals having three to about tenring carbon atoms, preferably three to about six carbon atoms, such ascyclopropyl and cyclobutyl. The terms "alkoxy" and "alkoxyalkyl" embracelinear or branched oxy-containing radicals each having alkyl portions ofone to about ten carbon atoms, such as methoxy group.

Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,iso-pentyl, methyl-butyl, dimethylbutyl and neopentyl.

Included within the family of compounds of the described are thetautomeric forms of the described compounds, isomeric forms includingdiastereoisomers and individual enantiomers, and thepharmaceutically-acceptable salts thereof. The term"pharmaceutically-acceptable salts" embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. Since the compounds contain basic nitrogen atoms, such salts aretypically acid addition salts. The phrase "pharmaceutically-acceptablesalts" is intended to embrace alkyl quaternary ammonium salts andn-oxides. The nature of the salt is not critical, provided that it ispharmaceutically acceptable, and acids which may be employed to formsuch salts are, of course, well known to those skilled in this art.Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid, and such organicacids as maleic acid, succinic acid and citric acid. Otherpharmaceutically acceptable salts include salts with alkali metals oralkaline earth metals, such as sodium, potassium, calcium and magnesium,or with organic bases, such as dicyclohexylamine. All of these salts maybe prepared by conventional means by reacting, for example, theappropriate acid or base with the corresponding compound of theinvention.

The compounds that are the subject of the invention herein can beprepared according to the following reaction schemes.

Z₁ is known and is prepared as described by Miyano and coworkers [J.Heterocyclic Chemistry (1987) 24, 47 for q=1; J. Pharmaceutical Sciences(1987), 76, 416 & references sited therein]. Z₂ is prepared according toschemes 1, 2, and 3.

Scheme 1 describes the preparation of amino-azacycles Z₂. The BOC-amine1 (U.S. patent application Ser. No. 07/515,391) is deprotected withtrifluoroacetic acid and the resulting amine is cyclizedintramolecularly with the exocyclic olefin by treatment with iodine andpotassium iodide in the presence of sodium bicarbonate to yield thebridgehead iodide 2. Treatment of 2 with silver isocyanate affords thebridgehead isocyanate which may be hydrolyzed to give the requisiteamine Z₂ wherein r=0. Alternatively treatment of 2 with silver cyanideaffords the bridgehead nitrile which may be reduced to give the desiredaminomethyl-azacycle Z₂ wherein r=1.

Scheme 2 illustrates the preparation of Z₂ hydroxy azacycles. Hydrolysisof bridgehead iodide 2 affords the desired hydroxy azacycle Z_(2")wherein r=0. Alternatively treatment of 2 with silver cyanade followedby hydrolysis and reduction gives the desired hydroxymethyl azacycleZ_(2'") wherein r=1.

Scheme 3 illustrates the preparation of ethano-bridged azatricycles(Z_(2""), wherein m=2). The azabicycloketone 3 is converted first to itsO-benzyloxime. Removal of the N-BOC protecting group, followed byacylation with chloroacetic anhydride & iodide exchange, affords theintermediate 4. Cyclization under reductive radical-cyclizationconditions (Bu₃ SnH, AIBN) affords the ethano-bridged lactam 5.Reduction with lithium aluminum hydride affords the desiredethano-bridged azatricycle Z_(2'").

Scheme 4 illustrates an alternative preparation of azacycle Z₂ (whereinr and m are each 1). The known 2-(1,1-dimethylethyl)-5,5-dimethylhexahydrocyclopenta[c]pyrrole-2,5,5-tricarboxylate 6 (Journal of OrganicChemistry, 1990, 55, 3673) is converted to the diol 7 by hydridereduction, preferably lithium borohydride in tetrahydrofuran. This diolis converted to a derivative 8 in which Q is a suitable leaving group(preferably tosylate: by reaction of the diol 7 with p-toluenesulfonylchloride/pyridine). Deprotection of the N-butoxycarbonyl moiety bytreatment with acid, preferably triflouroacetic acid, then affords thebis-tosylate amine 9. Reaction of 9 with a base, preferably cesiumcarbonate in dimethylformamide, gives the O-tosylated azatricycle 10.Reaction of 10 with sodium azide in a polar, aprotic solvent (preferablydimethylformamide or dimethylsulfoxide affords the azido-substitutedazatricycle 11, which is subjected to reduction, preferably lithiumaluminum hydride in tetrahydrofuran, to afford the desiredamino-substituted azatricycle Z₂ (r=m=1). ##STR10##

These examples, as well as all examples herein, are given by way ofillustration only and are not to be construed as limiting the invention,either in spirit or scope, as many modifications, both in materials andmethods, will be apparent from this disclosure to those skilled in theart. In these examples, temperatures are given in degrees Celsius (°C.)and quantities of materials in grams and milliliters unless otherwisenoted.

EXPERIMENTALS EXAMPLE A Preparation ofhexahydro-5-iodo-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrole ##STR11##

Cis-N-t-butoxycarbonylhexahydro-5-methylenecyclopenta[c]pyrrole [Seeco-pending application Ser. No. 07/515,391 filed Apr. 27, 1990] istreated with trifluoroacetic acid to afford an intermediatetrifluoroacetate ammonium salt, which is then treated with base and I₂to afford the title compound.

EXAMPLE B Preparation oftetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-amine##STR12##

The iodo compound prepared in example A is treated with silverisocyanate to afford the intermediate N-formamide. This formamide ishydrolyzed to give the title compound.

EXAMPLE C Preparation oftetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrole-5(3H)-carbonitrile##STR13##

The iodo compound prepared in example A is treated with silver cyanidein dimethylformamide to afford the title compound.

EXAMPLE D Preparation oftetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrole-5(3H)-methanamine##STR14##

The nitrile compound prepared in example C is reduced with lithiumaluminum hydride in etheral solvent to afford the title compound.

EXAMPLE E Preparation of tetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrole-5(3H)-methanol ##STR15##

The nitrile compound prepared in example C is converted to theintermediate ethyl ester by treatment with aqueous ethanolic HCl. Theethyl ester is then treated with lithium aluminum hydride in etheralsolvent to afford the title compound.

EXAMPLE F Preparation of 1,1-dimethylethylhexahydro-5-[(phenylmethoxy)imino]cyclopenta[c]pyrrole-2(1H)-carboxylate##STR16##

Cis-N-Butoxycarbonylhexahydro-5-oxo-cyclopenta[c]pyrrole is reacted with0-benzylhydroxylamine hydrochloride and sodium acetate in methanol toafford the title compound.

EXAMPLE G Preparation ofoctahydro-2-(iodoacetyl)-5[(phenylmethoxy)imino]cyclopenta[c]pyrrole##STR17##

The title compound of example F is treated with trifluoroacetic acid inmethylene chloride at room temperature. The volatiles are removed underreduced pressure to afford a residue which is treated with chloroaceticanhydride and triethylamine. The chloroacetylated material is thenreacted with NaI in acetone to give the title compound.

EXAMPLE H Preparation ofhexahydro-5-[(phenylmethoxy)amino]-2,5β-ethano-1H-3aα,6aα-cyclopenta[c]pyrrol-7-one##STR18##

The title compound of example G is treated with tri-n-butylstannane inbenzene at reflux containing a catalytic amount of AIBN. Upon workup thetitle compound is isolated.

EXAMPLE J Preparation oftetrahydro-2,5β-ethano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-amine##STR19##

The title compound of example H is reacted with lithium aluminum hydridein tetrahydrofuran to afford after workup the title compound.

EXAMPLE K Preparation of 1,1-dimethylethylhexahydro-5,5-bis(hydroxymethyl)cyclopenta[c]pyrrole-2(1H)-carboxylate##STR20##

The starting material, 2-(1,1-dimethylethyl)5,5-dimethylhexahydrocyclopenta[c]pyrrole-2,5,5-tricarboxylate, [For syntheticpreparation of this material see Flynn, D. L. and Zabrowski, D. L.,"Halogen Atom Transfer Annulations Involving Iodomalonates andAllylamine Derivatives," Journal of Organic Chemistry, 55, 1990,3673-3674] is treated with gradual addition of lithium borohydride intetrahydrofuran at room temperature. The solution is concentrated invacuo washed in water and extracted into chloroform to afford the titlecompound in 95% yield. This material is used without furtherpurification. ¹ HNMR (300 MHz, CDCl₃): δ=1.32 ppm (m, 2H); 1.45 (s, 9H);1.86 (m, 2H); 2.67 (m, 2H); 3.18 (m, 2H); 3.46 (m, 2H): 3.49 (d, 2H);3.60 (d, 2H); 4.36 (d, 2H).

EXAMPLE L Preparation of 1,1-dimethylethylhexahydro-5,5-bis[[[(4-methylphenyl)sulfonyl]oxy]methyl]cyclopenta[c]pyrrole-2(1H)-carboxylate##STR21##

The diol compound prepared in Example A is dissolved in pyridine andtreated with p-toluenesulfonyl chloride at -10° C., warmed to roomtemperature over two hours, diluted with aqueous sodium bicarbonate andextracted into chloroform to afford the title compound in 93% yield.This material is used without further purification. ¹ HNMR (400 MHz,CDCl₃): δ=1.26 ppm (m, 2H); 1.45 (s, 9H); 1.80 (m, 2H); 2.47 (s, 6H);2.59 (m, 2H); 3.10 (d, 2H); 3.39 (dd, 2H); 3.78 (s, 2H); 3.85 (s, 2H);7.36 (m, 4H); 7.72 (m, 4H).

EXAMPLE M Preparation ofhexahydrocyclopenta[c]pyrrole-5,5(1H)-dimethanol,bis(4-methylbenzenesulfonate)##STR22##

The carbamate prepared in Example B is treated with triflouroaceticacid, washed with aqueous potassium carbonate and extracted intochloroform to afford the title compound in 90% yield. This material isused without further purification. ¹ HNMR (400 MHz, CDCl₃): δ=1.05 ppm(dd, 2H); 1.88 (dd, 2H); 2.19 (s, 1H); 2.45 (s, 3H); 2.46 (s, 3H); 2.49(m, 2H); 2.65 (d, 2H); 2.73 (m, 2H); 4.82 (s, 2H); 4.87 (s, 2H); 7.33(dd, 4H); 7.72 (m, 4H).

EXAMPLE N Preparation ofhexahydro-2,5β-methano-1H-3aR,3aα,6aα-cyclopenta[c]pyrrole-5-methanol,4-methylbenzenesulfonate##STR23##

The bis tosylate prepared in Example M is dissolved indimethylformamide, treated with cesium carbonate and heated for 4 hoursat 80° C. Dimethylformamide is removed by vacuum distillation and theresidue washed with aqueous sodium hydroxide and extracted intochloroform to afford the title compound in 80% yield. This material isused without further purification. ¹ HNMR (300 MHz, CDCl₃): δ=1.15 ppm(m, 4H); 2.46 (s, 3H); 2.59 (m, 2H); 2.75 (m, 1H); 2.79 (s, 2H); 2.80(m, 1H); 2.87 (dd, 1H); 2.90 (dd, 1H); 3.72 (s, 2H); 7.34 (d, 2H); 7.76(d, 2H).

EXAMPLE P Preparation of5-(azidomethyl)hexahydro-2,5β-methano-1H-3aR,3aα,6aα-cyclopenta[c]pyrrole##STR24##

The azatricyclic tosylate prepared in Example N is dissolved indimethylformamide treated with sodium azide and heated at 70° C. foreight hours. After removal of dimethylformamide by vacuum distillationthe residue is washed with aqueous sodium hydroxide and extracted intochloroform to yield crude product. The title compound is purified bysilica gel chromatography eluting with ethanolic ammonia and chloroformresulting in 50% yield. ¹ HNMR (300 MHz, CDCl₃): δ=1.69 ppm (s, 4H);2.63 (m, 2H); 2.85 (dd, 2H); 2.88 (s, 2H); 2.91 (s, 1H); 2.96 (s, 1H).

EXAMPLE Q Preparation ofhexahydro-2,5β-methano-1H-3aR,3aα,6aα-cyclopenta[c]pyrrole-5-methaneamine##STR25##

The azide prepared in Example P is dissolved in tetrahydrofuran andreduced with lithium aluminum hydride at reflux for two hours. AfterFeiser work up, Reagents for Organic Synthesis by Lewis F. Feiser andMary Feiser, Vol. 1, p 584 (1967) John Wiley & Sons, and filtration thefiltrate is concentrated under reduced pressure to afford the titlecompound in quantitative yield. This material is used without furtherpurification. ¹ HNMR (300 MHz, CDCl₃): δ=1.63 ppm (m, 4H); 1.75 (m, 2H);2.49 (s, 2H); 2.58 (quint, 2H); 2.82 (dd, 2H); 2.84 (s, 2H); 2.90 (s,1H); 2.93 (s, 1H).

EXAMPLE 1 Preparation of4-amino-5-chloro-2-methoxy-N-(tetrahydro-1H-pyrrolizin-7a (5H)-ylmethyl)benzamide ##STR26##

4-Amino-5-chloro-2-methoxybenzoic acid (134 mg, 0.00095 moles) and1,1'-carbonyldi-imidazole (151 mg, 0.00095 moles) were suspended in theDMF (2.5 ml) and the mixture was stirred until solution occurred (threehours). At this time, tetrahydro-1H-pyrrolizin-7a(5H)-methylamine [amineJ. Het Chem 24, 47, 1987] (134 mg; 0.00095 moles) was added and themixture was stirred for 2 hours. Tlc 30% MeOH/CHCl₃ /1/10% NH₄ OHindicated that the reaction was complete. Concentration afforded aresidue which was purified by prep tlc chromatography, eluting with 15%MeOH/CHCl₃ /1/10% NH₄ OH to yield 73 mg (24%) of the product. Theresidue was converted to the HCl salt with MeOH/HCl.

    ______________________________________                                        Elements                                                                              Calc    Found                                                         ______________________________________                                        Carbon  53.63   53.57   C.sub.16 H.sub.22 ClN.sub.3 O.sub.2 * 0.7 HCl *                               0.5 H.sub.2 O                                         Hydrogen                                                                              6.67    6.66                                                          Nitrogen                                                                              11.73   11.54   MW 358.35                                             Chlorine                                                                              16.82   16.51                                                         ______________________________________                                    

EXAMPLE 1A4-Amino-5-chloro-2-methoxy-N-(tetrahydro-1H-pyrrolizin-7a(5H)-ylethyl)benzamide##STR27## Procedure

4-Amino-5-chloro-2-methoxybenzoic acid (1.0 g, 0.005 moles) and1,1'-carbonyldi-imidazole (892 mg, 0.00055 moles) were suspended in theDMF (10 ml) and the mixture was stirred until solution occurred (threehours). At this time, tetrahydro-1H-pyrrolizin-7a(5H)-ethylamine [amineHeterocycles 16, 755, 1981](771 mg; 0.005 moles) was added and themixture was stirred for 1 hour. Tlc 30% MeOH/CHCl₃ /1/10% NH₄ OHindicated that the reaction was complete. Concentration afforded aresidue which was partitioned between Et₂ O/H₂ O. The productcrystallized. The solid was filtered and dissolved in CHCl₃, washed withdilute K₂ CO₃, dried over MgSO₄ and concentrated to a solid. The solidwas triturated with Et₂ O and converted to the HCl salt with MeOH/HCl toyield 1.27 g (69%) of the product.

    ______________________________________                                        Elements                                                                      ______________________________________                                        Carbon     49.71  49.39    C.sub.17 H.sub.24 ClN.sub.3 O.sub.2 * 2 HCl        Hydrogen   6.38   6.46                                                        Nitrogen   10.23  10.18    MW 410.77                                          Chlorine   25.89  25.71                                                       ______________________________________                                    

EXAMPLE 1BN'-(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)-2-(2-propyloxy)phenylurea##STR28##

2-isopropoxy-aniline (123 mg, 0.813 mmole) was dissolved in CHCl₃ (1ml), added triethyl amine (0.113 ml, 0.813 mmole). Cooled soln. to 0°C., added a solution of 20%. phosgene in toluene (0.458 ml, 0.927 mmole)and stirred for 1.5 hours. To this solution was addedtetrahydro-1H-pyrrolizin-7a(5H)-methylamine (114 mgs, 0.813 mmole) inCHCl₃ and stirred for 18 hours. Solvent removed via rotary evaporator togive crude product as a solid. Solid was chromatographed on silica geleluting with 5% CH₃ OH(NH₃ ↑)/CHCl₃ to give 220 mg (85%) of titlecompound as free base.

    ______________________________________                                        Calculated for C.sub.18 H.sub.27 N.sub.2 O.sub.2 :                                                  Found                                                   C,         67.89          67.96                                               H,         8.86           8.61                                                N,         13.19          12.96                                               Calculated MS for C.sub.18 H.sub.23 N.sub.3 O.sub.2 =                                               318.44                                                  Found M =             318.215                                                 ______________________________________                                    

EXAMPLE 2 Preparation ofN-(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)-1H-indole-3-carboxamide##STR29##

Following the procedure of example 1,7a-Aminomethylhexahydro-1H-pyrrolizine is reacted withindole-3-carboxylic acid to afford the title compound.

Indole-3-carboxylic acid (161 mg, 0.001 moles) and1,1-carbonyldiimidazole (162 mg, 0.001 moles) were suspended in the DMF(2.5 ml) and the mixture was stirred until solution occurred (threehours). At this time, tetrahydro-1H-pyrrolizin-7a(5H)-methylamine [amineJ. Het Chem 24, 47, 1987] (140 mg; 0.001 moles) and triethylamine (560μl; 0.004 mole) were added and the mixture was stirred for 1 hour. Tlc30% EtOH/CHCl₃ /1/10% NH₄ OH indicated that the reaction was complete.Concentration afforded a residue that was partitioned between Et₂ O/H₂O. The product crystallized. The solid was filtered and dissolved inCHCl₃, washed with dilute NaOH, dried over MgSO₄ and concentrated to asolid. The solid was triturated with Et₂ O and converted to the HCl saltwith MeOH/HCl to yield 174 mg (62%) of the product.

    ______________________________________                                        Elements                                                                              Calc    Found                                                         ______________________________________                                        Carbon  62.98   62.68   C.sub.17 H.sub.21 N.sub.3 O * 0.75 HCl * 0.75                                 H.sub.2 O                                             Hydrogen                                                                              7.23    6.68                                                          Nitrogen                                                                              12.96   12.96   MW 324.23                                             Chlorine                                                                              8.20    8.31                                                          ______________________________________                                    

EXAMPLE 3 Preparation of2,3-dihydro-N-(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)-1H-indole-1-carboxamide##STR30##

7a-Aminomethylhexahydro-1H-pyrrolizine is reacted withindoline-N-trichloromethylcarbamate [J. Medicinal Chemistry (1990) 33:1929] in toluene at reflux to afford the title compound after extractiveworkup and column chromatography.

EXAMPLE 4 Preparation of1-methyl-N-(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)-1H-indazole-3-carboxamide##STR31##

Following the procedure of example 1,7a-Aminomethylhexahydro-1H-pyrrolizine is reacted withN-methylindazole-3-carboxylic acid [J. Medicinal Chemistry (1987) 30:1535] to afford the title compound.

EXAMPLE 5 Preparation of4-amino-5-chloro-2-methoxy-N-(tetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-yl)benzamide##STR32##

N-hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-5.alpha.-amineis reacted with 2-methoxy-4-amino-5-chlorobenzoic acid andcarbonyldiimidazole in dimethylformamide to afford the title compound.

EXAMPLE 6 Preparation ofN-(tetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-yl)-1H-indole-3-carboxamide##STR33##

N-hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-5.alpha.-amineis reacted with indole-3-carboxylic acid according to the procedure ofexample 5 to afford the title compound.

EXAMPLE 7 Preparation of1-methyl-N-(tetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-yl)-1H-indazole-3-carboxamide##STR34##

N-hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-5.alpha.-amineis reacted with N-methylindazole-3-carboxylic acid according to theprocedure of example 5 to afford the title compound.

EXAMPLE 8 Preparation of2,3-dihydro-N-(tetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H-yl)-1H-indole-3-carboxamide##STR35##

N-hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-5.alpha.-amineis reacted with indoline-N-trichloromethylcarbamate according to theprocedure of example 3 to afford the title compound.

EXAMPLE 9 Preparation of4-amino-5-chloro-N-[(hexahydro-2,5β-methano-1H-3aR,3aα,6a.alpha.-cyclopenta[c]pyrrol-5-yl)methyl]-2-methoxybenzamide##STR36##

A solution of 2-methoxy-4-amino-5-chlorobenzoic acid indimethylformamide is treated with 1,1-carbonyldiimidazole and theresultant imidazolide is reacted withtetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrole-5(3H)-methaneamine. The mixture is chromatographed on silica gel elutingwith ethanolic ammonia and chloroform to afford the title compound in56% yield. ¹ HNMR (400 MHz, CDCl₃): δ=1.70 ppm (m, 4H); 2.60 (quint,2H); 2.82 (dd, 2H); 2.88 (s, 2H); 2.90 (s, 1H); 2.95 (s, 1H); 3.29 (d,2H); 3.91 (s, 3H); 4.45 (s, 2H); 6.31 (s, 1H); 7.65 (t, 1H); 8.10 (s,1H).

EXAMPLE 10 Preparation ofN-[(hexahydro-2,5β-methano-1H-3aR,3aα,6aα-cyclopenta[c]pyrrol-5-yl)methyl]-1H-indole-3-carboxamide##STR37##

Indole-3-carboxylic acid is converted to the acid chloride intermediatein refluxing thionyl chloride and methylene chloride. After azeotropingexcess thionyl chloride with toluene this acid chloride intermediate isreacted withhexahydro-2,5β-methano-1H-3aR,3aα,6aα-cyclopenta[c]pyrrole-5-methaneaminein triethylamine and chloroform and chromatographed on silica geleluting with ethanolic ammonia and chloroform to afford the titlecompound in 18% yield. ¹ HNMR (300 MHz, CDCl₃): δ=1.70 ppm (m, 4H); 2.60(quint, 2H); 2.82 (dd, 2H); 2.88 (s, 2H); 2.90 (s, 1H); 2.95 (s, 1H);3.30 (d, 2H); 6.32 (t, 1H); 7.22 (dd, 2H); 7.39 (dd, 1H); 7.80 (m, 1H);7.93 (m, 1H).

A. In Vitro Functional Assay for Serotonin 5-HT₄ agonism: RAT TMM

Serotonin 5-HT₄ agonism was measured in the rat esophagus in vitropreparation as reported by Baxter et al (Naunyn. Schmied. Arch.Pharmacol. 1991, 343, 439). Agonist activity was determined utilizingrelaxation of carbachol-contracted rat tunica muscularis mucosae. One 2cm segment of intrathoracic esophagus proximal to the diaphragm wasremoved from male rats, weighing approximately 300 gm, and the outermuscle layers removed. The inner tunica muscularis mucosa was mountedunder 0.2-0.3 g of tension in a tissue bath containing oxygenatedTyrode's solution at 37° C. Cortisterone acetate (30 μM) and fluoxetine(1 μM) were included in the buffer to prevent uptake of serotonin, aswell as pargyline (10 μM) to inhibit monoamine oxidase. Following a 30min equilibrium period, tissues were isometrically contracted withcarbachol (3 μM) to obtain a tonic contraction. A stable plateau wasobtained within 20 min when test compound was added cumulatively torelax the muscle strip. EC₅₀ values were obtained for each agonist intissues from 5 rats. EC₅₀ values for agonists at this 5-HT₄ receptor areindicated as follows for the indicated compounds:

    ______________________________________                                               Example 1                                                                             422 nM                                                                Example 9                                                                             216 nM                                                         ______________________________________                                    

The compounds herein exhibit 5-HT3 antagonism. 5-HT3 antagonism can bedetermined by the radioligand receptor binding assay as described hereinand in the in vivo Bezold-Jarisch reflex procedure.

Serotonin (5-HT₃)

Procedure:

GR65630 binds to the 5-HT₃ receptor. Brain cortices are obtained frommale rats and a membrane fraction prepared by standard techniques. 0.04mg of membrane prep is incubated with 0.2 nM [³ H]-GR656630 for 60minutes at 22° C. Non-specific binding is estimated in the presence of 1uM ICS 205-930. Membranes are filtered and washed 3 times and thefilters are counted to determine [3H]-GR65630 specifically bound.*

Kilpatrick G. J., Jones B. J. and Tyers M. B. Identification anddistribution of 5-HT₃ receptors in rat brain using radioligand binding.Nature, 330: 746-748, 1987.

Results:

Kd=2.46 nM

Bmax=154 fmol/mg protein

% Specific Binding: 70

    ______________________________________                                        Effect of Reference Compounds on                                              [H]-GR65630 Bound (0.2 nM)                                                    Compound   IC.sub.50  Ki       Hill Coefficient                               ______________________________________                                        Quipazine   0.5 nM    0.18 nM  0.86                                           ICS 205-930                                                                               2.2 nM    0.51 nM  1.0                                            5-HT        122 nM    0.39 nM  1.0                                            RU24969     320 nM    1.85 nM  1.0                                            Zacopride  0.55 nM    0.18 nM  0.86                                           ______________________________________                                    

Bezold-Jarisch Reflex

The test sample is administered i.p. (mg/kg) to a group of 3 mice.Thirty minutes later, a 5-HT (0.25 mg/kg i.v.)--induced bradycardia isrecorded in pentobarbital anesthetized animals. A greater than 50percent (>50) reduction in the bradycardic response relative tovehicle-treated control mice is considered significant.

    ______________________________________                                                         Minimum Effective Dose                                       REFERENCE AGENTS:                                                                              (MED) mg/kg                                                  ______________________________________                                        BRL-43694        0.05                                                         cisapride        5                                                            cyproheptadine   5                                                            domperidone      >10                                                          GR-38032         0.5                                                          ketanserin       >10                                                          mecamylamine     2.5                                                          methysergide     >10                                                          metoclopramide   5                                                            scopolamine      2.5                                                          ______________________________________                                    

This method has been described by Saxena, P. R. and Lawang, A., Arch.Int. Pharmacodyn., 277:235-252, 1985.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more of the described compounds inassociation with one or more nontoxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. Therapeutically effective doses of the compounds ofthe present invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art. The compounds and composition may, for example, be administeredintravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 250 mg,preferably from about 25 to 150 mg. A suitable daily dose for a mammalmay vary widely depending on the condition of the patient and otherfactors. However, a dose of from about 0.1 to 3000 mg/kg body weight,particularly from about 1 to 100 mg/kg body weight, may be appropriate.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If administered per os, the compounds may be admixedwith lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. A compound of the formula ##STR38## thestereoisomers and pharmaceutically acceptable salts thereof, wherein A₁is O, S, N (R₁₂) or CH₂ ;X is NH or O; R₄ is selected from the groupconsisting of H, halogen and C₁₋₆ alkoxy; R₁₂ is selected from the groupconsisting of H, C₁₋₆ alkyl and aralkyl; and Z represents a radical ofthe formula: ##STR39## wherein m is 1 or 2, q is 1 or 2 and r is 0 or 1.2. A compound according to claim 1 wherein Z is Z₁.
 3. A compoundaccording to claim 1 wherein Z is Z₂.
 4. A compound according to claim 1wherein Ar is indol-3-yl.
 5. A compound according to claim 4 wherein Zis Z₁.
 6. A compound according to claim 4 wherein Z is Z₂.
 7. Apharmaceutical composition for treatment of anxiety, psychoses,depression, gastrointestinal motility disturbances or conditionsresponsive to a 5-HT₃ effect comprising a therapeutically effectiveamount of a compound as defined in claim 1 and a pharmaceuticallyacceptable carrier or diluent.
 8. A pharmaceutical composition accordingto claim 7 wherein A₁ is CH₂.